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The roles of macrophage migration inhibitory factor in retinal diseases

Neural Regeneration Research 2024年第2期19卷 309-315页

作者： Hongbing Zhang Xianjiao Zhang Hongsong Li Bing Wang Pei Chen Jiamin Meng Shaanxi Institute of Ophthalmology Xi’anShaanxi ProvinceChina Department of Ophthalmology First Affiliated Hospital of Northwest UniversityXi’anShaanxi ProvinceChina Department of Pathology First Affiliated Hospital of Northwest UniversityXi’anShaanxi ProvinceChina

Macrophage migration inhibitory factor(MIF),a multifunctional cytokine,is secreted by various cells and participates in inflammatory reactions,including innate and adaptive immunity.There are some evidences that MIF is involved in many vitreoretinal diseases.For example,MIF can exacerbate many types of uveitis;measurements of MIF levels can be used to monitor the effectiveness of uveitis treatment.MIF also alleviates trauma-induced and glaucoma-induced optic nerve damage.Furthermore,MIF is critical for retinal/choroidal neovascularization,especially complex neovascularization.MIF exacerbates retinal degeneration;thus,anti-MIF therapy may help to mitigate retinal degeneration.MIF protects uveal melanoma from attacks by natural killer cells.The mechanism underlying the effects of MIF in these diseases has been demonstrated:it binds to cluster of differentiation 74,inhibits the c-Jun N-terminal kinase pathway,and triggers mitogen-activated protein kinases,extracellular signal-regulated kinase-1/2,and the phosphoinositide-3-kinase/Akt pathway.MIF also upregulates Toll-like receptor 4 and activates the nuclear factor kappa-B signaling pathway.This review focuses on the structure and function of MIF and its receptors,including the effects of MIF on uveal inflammation,retinal degeneration,optic neuropathy,retinal/choroidal neovascularization,and uveal melanoma.

关键词： diabetic retinopathy glaucoma macrophage migration inhibitory factor migration inhibitory factor receptor optic neuropathy retinal degeneration retinal neovascular uveal melanoma uveitis

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Cell replacement with stem cell-derived retinal ganglion cells from different protocols

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Neural Regeneration Research 2024年第4期19卷 807-810页

作者： Ziming Luo Kun-Che Chang Spencer Center for Vision Research Byers Eye InstituteStanford University School of Medicine Department of Ophthalmology Louis J.Fox Center for Vision RestorationUniversity of Pittsburgh School of Medicine Department of Neurobiology Center of NeuroscienceUniversity of Pittsburgh School of Medicine

Glaucoma,characterized by a degenerative loss of retinal ganglion cells,is the second leading cause of blindness worldwide.There is currently no cure for vision loss in glaucoma because retinal ganglion cells do not regenerate and are not replaced after injury.Human stem cell-derived retinal ganglion cell transplant is a potential therapeutic strategy for retinal ganglion cell degenerative diseases.In this review,we first discuss a 2D protocol for retinal ganglion cell differentiation from human stem cell culture,including a rapid protocol that can generate retinal ganglion cells in less than two weeks and focus on their transplantation outcomes.Next,we discuss using 3D retinal organoids for retinal ganglion cell transplantation,comparing cell suspensions and clusters.This review provides insight into current knowledge on human stem cell-derived retinal ganglion cell differentiation and transplantation,with an impact on the field of regenerative medicine and especially retinal ganglion cell degenerative diseases such as glaucoma and other optic neuropathies.

关键词： cell clumps cell suspension cell transplantation differentiation direct-induced protocol glaucoma optic neuropathy regenerative medicine retinal ganglion cell retinal organoids stem cells

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The concept of gene therapy for glaucoma:the dream that has not come true yet

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Neural Regeneration Research 2024年第1期19卷 92-99页

作者： Robert Sulak Xiaonan Liu Adrian Smedowski Department of Physiology Faculty of Medical Sciences in KatowiceMedical University of Silesia in KatowiceKatowicePoland Institute of Biotechnology HiLIFEUniversity of HelsinkiHelsinkiFinland GlaucoTech Co. KatowicePoland

Gene therapies,despite of being a relatively new therapeutic approach,have a potential to become an important alternative to current treatment strategies in glaucoma.Since glaucoma is not considered a single gene disease,the identified goals of gene therapy would be rather to provide neuroprotection of retinal ganglion cells,especially,in intraocular-pressure-independent manner.The most commonly reported type of vector for gene delivery in glaucoma studies is adeno-associated virus serotype 2 that has a high tro pism to retinal ganglion cells,res ulting in long-term expression and low immunogenic profile.The gene thera py studies recruit inducible and genetic animal models of optic neuropathy,like DBA/2J mice model of high-tension glaucoma and the optic nerve crush-model.Reported gene therapy-based neuroprotection of retinal ganglion cells is targeting specific genes translating to growth factors(i.e.,brain derived neurotrophic factor,and its receptor TrkB),regulation of apoptosis and neurodegeneration(i.e.,Bcl-xl,Xiap,FAS system,nicotinamide mononucleotide adenylyl transferase 2,Digit3 and Sarm1),immunomodulation(i.e.,Crry,C3 complement),modulation of neuroinflammation(i.e.,e rythropoietin),reduction of excitotoxicity(i.e.,Com KIlα)and transcription regulation(i.e.,Max,Nrf2).On the other hand,some of gene therapy studies focus on lowering intra ocular pressure,by impacting genes involved in both,decreasing aqueous humor production(i.e.,aquaporin 1),and increasing outflow facility(i.e.,COX2,prostaglandin F2a receptor,RhoA/RhoA kinase signaling pathway,MMP1,Myocilin).The goal of this review is to summarize the current stateof-art and the direction of development of gene therapy strategies for glaucomatous neuropathy.

关键词： adeno-associated virus gene editing gene therapy glaucoma IOP lowering IOP-independent mechanisms neuroprotection optic nerve optic neuropathy retinal ganglion cells

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Outbreak of methanol-induced optic neuropathy in early COVID-19 era;effectiveness of erythropoietin and methylprednisolone therapy

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World Journal of Clinical Cases 2023年第15期11卷 3502-3510页

作者： Seyed Ali Tabatabaei Mohammad Amini Ali A Haydar Mohammad Soleimani Kasra Cheraqpour Mansoor Shahriari Hossein Hassanian-Moghaddam Nasim Zamani Mohammad Reza AkbariDepartment of Ophthalmology Eye Research Center Farabi Eye Hospital Tehran University of Medical SciencesTehran ***Iran Department of Ophthalmology Imam Hossein Medical CenterShahid Beheshti University of Medical SciencesTehran ***Iran Department of Clinical Toxicology Shohada-e-Tajrish HospitalShahid Beheshti University of Medical SciencesTehran ***Iran Department of Internal Medicine StreetAgnes Medical CenterFresnoCA 93720United States

BACKGROUND Methanol is a highly toxic,non-potable alcohol.Outbreaks of methanol toxicity occur due to its fraudulent addition to alcoholic beverages as a cheaper substitute for ethanol.Recently,alongside the coronavirus disease 2019(COVID-19)pandemic,rumors circulated on social media that consuming alcohol can prevent or cure the virus,leading to a COVID-19 and methanol-induced optic neuropathy(MON)syndemic.AIM To investigate the impact of erythropoietin(EPO)on the outcomes of patients diagnosed with MON.METHODS In this prospective study,105 patients presenting with acute bilateral visual loss secondary to methanol intoxication were enrolled from March to May 2020 at Farabi Eye Hospital.A comprehensive ocular examination was conducted for all participants.Recombinant human EPO and methylprednisolone were administered intravenously to all patients for three consecutive days.RESULTS The mean age of the participants was 39.9 years(±12.6).Ninety-four patients were male and eleven were female.The mean pre-treatment best corrected visual acuity(BCVA)improved from 2.0±0.86 to 1.39±0.69 logarithm of the minimum angle of resolution post-treatment(P<0.001),with significant improvement observed in all age categories and genders(P<0.001).Visual acuity improvement was also significant regardless of whether the patient presented before or after 72 h(P<0.001),and the post-treatment BCVA remained significant at all monthly follow-up visits(P<0.001).CONCLUSION EPO and methylprednisolone therapy have been shown to be effective in improving visual outcomes in patients with MON when administrated within the first month of exposure.Public awareness efforts are necessary to prevent further outbreaks of methanol toxicity in the current COVID-19 era.

关键词： Alcohol Ethanol Methanol optic neuropathy Erythropoietin COVID-19

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Small extracellular vesicles derived from human induced pluripotent stem cell-differentiated neural progenitor cells mitigate retinal ganglion cell degeneration in a mouse model of optic nerve injury

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Neural Regeneration Research 2025年第2期20卷 587-597页

作者： Tong Li Hui-Min Xing Hai-Dong Qian Qiao Gao Sheng-Lan Xu Hua Ma Zai-Long Chi State Key Laboratory of Ophthalmology Optometry and Visual ScienceEye HospitalWenzhou Medical UniversityWenzhouZhejiang ProvinceChina National Clinical Research Center for Ocular Diseases Eye HospitalWenzhou Medical UniversityWenzhouZhejiang ProvinceChina

Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application.Small extracellular vesicles(sEVs)contain bioactive molecules for neuronal protection and regeneration.Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases.In this study,we intravitreally transplanted sEVs derived from human induced pluripotent stem cells(hiPSCs)and hiPSCs-differentiated NPCs(hiPSC-NPC)in a mouse model of optic nerve crush.Our results show that these intravitreally injected sEVs were ingested by retinal cells,especially those localized in the ganglion cell layer.Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration,and regulated the retinal microenvironment by inhibiting excessive activation of microglia.Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells,which had protective effects on RGCs after optic nerve injury.These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.

关键词： exosome miRNA neural progenitor cell neurodegeneration neuroinflammation neuroprotection optic nerve crush optic neuropathy retinal ganglion cell small extracellular vesicles

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Stem Cell Ophthalmology Treatment Study(SCOTS) for retinal and optic nerve diseases: a case report of improvement in relapsing auto-immune optic neuropathy

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Neural Regeneration Research 2015年第6期10卷 1507-1515页

作者： Jeffrey N.Weiss Steven Levy Susan C.Benes Retina Associates of South Florida MD Stem Cells Wilmer Eye Institute The Johns Hopkins Hospital

We present the results from a patient with relapsing optic neuropathy treated within the Stem Cell Ophthalmology Treatment Study （SCOTS）. SCOTS is an Institutional Review Board ap- proved clinical trial and has become the largest ophthalmology stem cell study registered at the National Institutes of Health to date （www.***.gov Identifier NCT 01920867）. SCOTS utilizes autologous bone marrow-derived stem cells （BMSCs） for treatment of retinal and optic nerve diseases. Pre-treatment and post-treatment comprehensive eye exams of a 54 year old female patient were performed both at the Florida Study Center, USA and at The Eye Center of Columbus, USA. As a consequence of a relapsing optic neuritis, the patient＇s previously normal visual acuity decreased to between 20/350 and 20/400 in the right eye and to 20/70 in the left eye. Significant visual field loss developed bilaterally. The patient underwent a right eye vitrectomy with injection of BMSCs into the optic nerve of the right eyeand retrobulbar, subtenon and in- travitreal injection of BMSCs in the left eye. At 15 months after SCOTS treatment, the patient＇s visual acuity had improved to 20/150 in the right eye and 20/20 in the left eye. Bilateral visual fields improved markedly. Both macular thickness and fast retinal nerve fiber layer thickness were maximally improved at 3 and 6 months after SCOTS treatment. The patient also reduced her mycophenylate dose from 1,500 mg per day to 500 mg per day and required no steroid pulse therapy during the 15-month follow up.

关键词： nerve regeneration stem cells optic nerve autoimmune optic neuropathy ophthalmology bone marrow-derived stem cells blindness visual loss Stem Cell Ophthalmology Treatment Study neural regeneration

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Stem Cell Ophthalmology Treatment Study (SCOTS)： bone marrow-derived stem cells in the treatment of Leber＇s hereditary optic neuropathy

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Neural Regeneration Research 2016年第10期11卷 1685-1694页

作者： Jeffrey N. Weiss Steven Levy Susan C. Benes Retina Associates of South Florida 5800 Colonial Drive Suite 300 Margate FL USA MD Stem Cells 3 Sylvan Road South Westport CT USA The Eye Center of Columbus The Ohio State University Columbus OH USA

The Stem Cell Ophthalmology Treatment Study （SCOTS） is currently the largest-scale stem cell ophthal- mology trial registered at ClinicalTrials.gov （identifier： NCT01920867）. SCOTS utilizes autologous bone marrow-derived stem cells （BMSCs） to treat optic nerve and retinal diseases. Treatment approaches include a combination of retrobulbar, subtenon, intravitreal, intra-optic nerve, subretinal, and intravenous injection of autologous BMSCs according to the nature of the disease, the degree of visual loss, and any risk factors related to the treatments. Patients with Leber＇s hereditary optic neuropathy had visual acuity gains on the Early Treatment Diabetic Retinopathy Study （ETDRS） of up to 35 letters and Snellen acuity improvements from hand motion to 20/200 and from counting fingers to 20/100. Visual field improvements were noted. Macular and optic nerve head nerve fiber layer typically thickened. No serious complications were seen. The increases in visual acuity obtained in our study were encouraging and suggest that the use of autolo- gous BMSCs as provided in SCOTS for ophthalmologic mitochondrial diseases including Leber＇s hereditary optic neuropathy may be a viable treatment option.

关键词： nerve regeneration Leber＇s hereditary optic neuropathy mitochondrial disease optic neuropathy bone marrow derived stem cells blindness visual loss neural regeneration

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Protective effects of Rutin against methanol induced acute toxic optic neuropathy：an experimental study

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International Journal of Ophthalmology(English edition) 2018年第5期11卷 780-785页

作者： Nurdan Gamze Tasli Ferda Keskin Cimen Yücel Karakurt Turgay Ucak Renad Mammadov Bahadir Suleyman Nezahat Kurt Halis Suleyman Department of Ophthalmology Erzincan University HospitalCollege of Medicine Erzincan 24100 Turkey Department of Pathology Erzincan University HospitalCollege of Medicine Erzincan 24100 Turkey Department of Pharmacology Erzincan University HospitalCollege of Medicine Erzincan 24100 Turkey Department of Biochemistry Ataturk University HospitalCollege of Medicine Erzurum 25100 Turkey

AIM：To determine the effects of Rutin on methanol induced optic neuropathy and compare the results with the effects of ethanol.METHODS：Totally 30 rats were divided into 5 groups,with 6 rats in each group as follows：healthy controls（C）,methotrexate（MTX）,methotrexate＋methanol（MTM）,methotrexate＋methanol＋ethanol（MTME） and methotrexate＋ methanol＋Rutin（MTMR）.In all rabbits except those of the control group,MTX,diluted in sterile serum physiologic,0.3 mg/kg per oral was applied for 7 d by the aid of a tube.After this procedure to the rats of MTM,MTME and MTMR groups,20% methanol with a dose of 3 g/kg per oral was given by the aid of a tube.In MTME group,4 h after the application of methanol,20% ethanol was applied by the same way with a dose of 0.5 g/kg.On the other hand,in MTMR group 4 h after the application of methanol,Rutin,which was dissolved in distilled water,was applied by the same way with a dose of 50 mg/kg.RESULTS：There were statistically significant differences in tissue 8-hydroxy-2 deoxyguanine（8-OHdG）,interleukin-1β（IL-1β）,tumor necrosis factor-alpha（TNF-α）,malondialdehyde（MDA）,myeloperoxidase（MPO）.glutathione peroxidase（t GSH） and superoxide dismutase（SOD） levels between groups（P〈0.001）.In MTMR group tissue 8-OHdG,IL-1β,MDA,and MPO levels were similar with the healthy controls but significantly different than the other groups.In histopathological evaluations,in MTX group there was moderate focal destruction,hemorrhage and decrease innumber of astrocytes and oligodendrocytes;in MTM group there was severe destruction and edema with decrease in number of astrocytes and oligodendrocytes;in MTME group there was mild hemorrhage,mild edema,mildly dilated blood vessels with congestion while in MTMR group,optic nerve tissue was resembling the healthy controls.CONCLUSION：Rutin may prevent methanol-induced optic neuropathy via anti-inflammatory effects and decreasing the oxidative stress.New treatment options are warranted in this disease to avoid loss of vision in patients.

关键词： methanol optic neuropathy mtin astrocyte rat

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Clinical characteristics of progressive nonarteritic anterior ischemic optic neuropathy

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International Journal of Ophthalmology(English edition) 2021年第4期14卷 517-522页

作者： Omer Y.Bialer Hadas Stiebel-Kalish Neuro Ophthalmology Unit Ophthalmology DepartmentRabin Medical CenterPetah Tikva 4941492Israel Sackler School of Medicine Tel Aviv UniversityTel Aviv 6997801Israel

AIM:To study whether patients with progressive nonarteritic anterior ischemic optic neuropathy(NAION)present earlier than patients with stable NAION and to describe their clinical characteristics and visual outcome.METHODS:This was a retrospective chart review.All patients with NAION seen during the acute stage from January 2012 to December 2018 were reviewed.Patients were included if they had documented disc edema and follow up of at least 3 mo.Patients with progressive NAION were identified if they worsened in 2 out of 3 parameters:visual acuity≥3 Snellen lines;Color vision≥4 Ishihara plates;the visual field defect involved a new quadrant.The clinical characteristics,time from symptom onset to presentation,systemic risk factors and visual outcome were compared to patients with stable NAION.RESULTS:Totally 122 NAION cases met the inclusion criteria.Mean age was 58.1 y(range 22-74),70%were men.Twenty cases(16.4%)had progressive NAION.Patients with progressive NAION did not differ from stable NAION in their demographics,systemic risk factors or in their initial visual deficit.At last follow up,median visual acuity was 1.0 log MAR(IQR 0.64-1.55)in patients with progressive NAION,vs 0.18(IQR 0.1-0.63)in stable NAION(P<0.001).Median color vision testing was 0 plates correct(IQR 0-2.5%)vs 92%plates correct(IQR 50%-100%)in the stable NAION group(P<0.001).Patients with progressive NAION differed in the time from symptom onset to presentation(median 2 d vs 5 d,P=0.011).CONCLUSION:We find no identifiable risk factors associated with progressive NAION.Progressors arrive earlier for ophthalmological evaluation.

关键词： nonarteritic anterior ischemic optic neuropathy optic neuropathy disc edema visual field defect

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Different damage patterns of retinal nerve fiber layer and ganglion cell-inner plexiform layer between early glaucoma and non-glaucomatous optic neuropathy

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International Journal of Ophthalmology(English edition) 2020年第6期13卷 893-901页

作者： Hui Xiao Xing Liu Ping Lian Ling-Ling Liao Yi-Min Zhong State Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangzhou 510060Guangdong ProvinceChina

AIM:To compare the damage pattern of the peripapillary retinal nerve fiber layer(pRNFL)and the macular ganglion cell-inner plexiform layer(mGCIPL)between early glaucomatous and non-glaucomatous optic neuropathy(EGON and NGON).METHODS:It is a cross-sectional study.Thirty-eight healthy controls,74 EGONs and 70 NGONs with comparable average pRNFL loss were included.The NGON group included 23 eyes of optic neuritis(ON),13 eyes of hereditary optic neuropathy(HON),19 eyes of toxic optic neuropathy(TON)and 15 eyes of compressive neuropathy(CON).The sectoral pRNFL and mGCIPL thickness obtained by high definition optical coherence tomography were analyzed.RESULTS:Compared to normal controls,the pRNFL thickness in all quadrants showed a decrease in both EGON and NGON group(P0.05).The mGCIPL of EGON and NGON group were thinner than control group(P<0.001).In EGON group the severest sites of mGCIPL reduction was located at inferotemporal and inferior sectors.While,compared to EGON group,the average mGCIPL of NGON groupwere significantly thinner,especially in superonasal and inferonasal sectors(P<0.001).CONCLUSION:The damage pattern of pRNFL and mGCIPL caused by glaucoma is distinct from other NGON such as ON,TON,HON and CON,and this characteristic damage pattern is helpful in differentiating early glaucoma from other NGON.

关键词： glaucoma optic neuropathy retinal nerve fiber layer ganglion cell-inner plexiform layer optical coherence tomography

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